Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>Increasing evidence suggests that histone post-translational modifications (PTMs) function in combination to regulate the diverse activities associated with chromatin. However, the mechanisms through which multiple histone PTMs influence the association of effector proteins with chromatin is poorly understood. To address this problem, we recently developed a histone peptide array platform containing singly- and multiply-modified histone peptides to examine the binding of chromatin-associated proteins. Using these arrays, we surveyed protein domains that bound methylated H3K9, and uncovered a number of PTM “patterns” that influenced the association with this mark. Interestingly, while most H3K9 methyl binders were ejected by neighboring H3S10 phosphorylation (a PTM enriched in G2/M-phase chromatin), the tandem Tudor domain (TTD) of UHRF1 was insensitive to this known “phospho/methyl switch”. In agreement, structural and biophysical studies confirmed the insensitivity of the UHRF1 TTD to H3S10 phosphorylation. Furthermore, we found that UHRF1 remains bound to chromatin throughout the cell cycle in contrast to HP1, which is ejected from chromatin during mitosis. These results suggest an important role for this ubiquitin ligase during mitosis. Significantly, we further find that the TTD of UHRF1 regulates global DNA methylation, thus definitively linking H3K9me3 binding by UHRF1 to the maintenance of DNA methylation. Taken together, our data suggest that the regulation of DNA methylation by UHRF1 extends beyond S-phase and requires H3K9me3 recognition during mitosis.</jats:p>
<jats:p>Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 993. doi:1538-7445.AM2012-993</jats:p>